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Eco-friendly and Enantiospecific Biginelli Synthesis Using (+)-Myrtenal as the Substrate - An Impeccable and Unequivocal Analysis of the Product.
Current Organic Synthesis ( IF 1.8 ) Pub Date : 2020-07-31 , DOI: 10.2174/1570179417666200506103137
Luiza Albino Dias Benincá 1 , Carolina Bastos Pereira Ligiéro 1 , Jonas da Silva Santos 1 , Joel Jones Junior 1 , Flavia Martins da Silva 1
Affiliation  

Background: We found in the literature, an excellent review of the Biginelli reaction that addresses the methodologies for obtaining enantiopure dihydropyrimidinones (DHPMs). In 1992, optically pure DHPMs were obtained by fractional crystallization of the diastereomeric ammonium salt derivative with (S)-(-) and (R)- (+)-α-methyl benzylamine and by other chiral resolution techniques, such as chiral high-performance liquid chromatography (HPLC). Asymmetric syntheses of these compounds are also explained in the literature. The main strategy is to use acid catalysts such as organophosphates, organometallic complexes, amines and diamines, nanocomposites, and chiral ionic liquids, e.g., L-prolinium sulfate (Pro2SO4).

Objective: The objective was to study the Biginelli reaction with a chiral aldehyde.

Methods: A mixture of ethyl acetoacetate (0.26 g, 3 mmol), urea (0.18 g, 3 mmol) and ethyl lactate (EL) (1 mL) was left under heating at 70°C and stirring for 1 h. Next, (-)-(1R)-myrtenal (0.45 g, 3 mmol) was added, and the medium was heated for 5 h more until the formation of a white solid. Ten millilitres of distilled water was added, and the product was extracted with CH2Cl2 (3 x 4 mL). The solvent was evaporated, and the product was recrystallized from ethanol-water.

Results and Discussion: (+)-Myrtenal was used as a chiral substrate for a study that led to ethyl (R)-4-((1R,5S)- 6,6-dimethylbicyclo [3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate by the Biginelli synthesis using EL as a green solvent. The result is the first example of the enantiospecific Biginelli reaction. The product was exhaustively characterized by several physical analysis methods, i.e., 1H, 13C and 2D nuclear magnetic resonance (NMR) spectroscopies, infrared (IR) spectroscopy, mass spectrometry (MS), and high-resolution MS (HRMS), and its structure was unequivocally elucidated by X-ray crystallography.

Conclusion: Compound (4R)-4-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4- tetrahydropyrimidine- 5-ethyl carboxylate is the first example of the enantiospecific Biginelli reaction. In addition, the process has the advantage of using EL as a green solvent. The product was characterized by 1H, 13C, and 2D NMR and IR spectroscopy, MS, HRMS, and X-ray crystallography.



中文翻译:

使用(+)-Myrtenal作为底物的环保友好型对映体Biginelli合成-产品的无懈可击和明确分析。

背景:我们在文献中发现了Biginelli反应的出色综述,该反应涉及获得对映纯二氢嘧啶酮(DHPM)的方法。1992年,通过将非对映铵盐衍生物与(S)-(-)和(R)-(+)-α-甲基苄基胺分馏并通过其他手性拆分技术(例如手性高-高效液相色谱法(HPLC)。这些化合物的不对称合成在文献中也有解释。主要策略是使用酸催化剂,例如有机磷酸盐,有机金属配合物,胺和二胺,纳米复合材料和手性离子液体,例如硫酸L-脯氨酸(Pro2SO4)。

目的:研究手性醛与Biginelli的反应。

方法:将乙酰乙酸乙酯(0.26 g,3 mmol),尿素(0.18 g,3 mmol)和乳酸乙酯(EL)(1 mL)的混合物在70°C加热下搅拌1小时。接下来,添加(-)-(1R)-myrtenal(0.45g,3mmol),并将介质再加热5h直至形成白色固体。加入十毫升蒸馏水,产物用CH 2 Cl 2(3×4mL)萃取。蒸发溶剂,并将产物从乙醇-水中重结晶。

结果与讨论:(+)-Myrtenal被用作手性底物,可导致乙基(R)-4-((1R,5S)-6,6-二甲基双环[3.1.1] hept-2-en使用EL作为绿色溶剂,通过Biginelli合成,通过-2-in)-6-甲基-2-oxo-1,2,3,4-四氢嘧啶-5-羧酸酯。结果是对映体特异性Biginelli反应的第一个例子。通过几种物理分析方法(包括1H,13C和2D核磁共振(NMR)光谱,红外(IR)光谱,质谱(MS)和高分辨率MS(HRMS))对产品进行了详尽的表征。 X射线晶体学清楚地阐明了这一点。

结论:化合物(4R)-4-(6,6-二甲基双环[3.1.1]庚-2-烯-2-基)-6-甲基-2-氧代-1,2,3,4-四氢嘧啶-5 -羧酸乙酯是对映体特异性Biginelli反应的第一个例子。另外,该方法具有使用EL作为绿色溶剂的优点。通过1 H,13 C和2 D NMR和IR光谱,MS,HRMS和X射线晶体学对产物进行表征。

更新日期:2020-07-28
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